Similarities in the physical and chemical propertiis of the phosphoribosyltransferase (PRTase) family of enzymes suggest that they may share common structural features as observed in other functionally related proteins. The unusually high incidence of structural gene mutations of these enzymes in man are associated with several metabolic diseases of purine and pyrimidine metabolism. It is proposed that these disorders are the consequence of the structural instability of an architectural domain common to all of the PRTases. To investigate this hypothesis, the high resolution structures of hypoxanthine-guanine PRTase, adenine PRTase and quinolinate PRTase will be determined by X-ray diffraction analysis. These enzymes were selected for study based on their relevance to the deficiency diseases of purine and pyrimidine metabolism. Additionally, a structural investigation of a human kinetic mutant of HGPRTase will be initiated to determine the three-dimensional consequence of a point mutation. The technique of multiple isomorphous replacement will be used for the solution of HGPRTase, APRTase and QPRTase. The application of molecular replacement should facilitate the solution of the mutant HGPRTase enzyme.